Human physiologic systems
fluctuate in a cyclic manner, reflecting an internal awareness of diurnal and
seasonal cycles. The pineal supplies both clock and calendar information to the
organism.

Although the pattern of
nocturnal melatonin production varies among species, the duration of night-time
melatonin elevation is always proportional to the duration of night. Because the
duration of day and night changes during the year, photoperiod information is
information about time of year as well.

To survive the cyclic
variations, terrestrial organisms need mechanisms not just for detecting changes
in the environment but also for anticipating them. In the absence of an explicit
environmental cue, organisms needed an internal signal of impending change to
make timely, adaptive behavioural preparations.

The organism must respond
appropriately to cycles and oscillations of variable frequency and amplitude. In
addition to the light­dark cycle, there are cycles of reproduction, seasons and
aging (the cycle from birth to death). Virtually all of the multifarious pineal
physiologic functions can be understood in the context of vertebrate biological
cycles.

Signal Transduction

Cyclic environmental stimuli
affect the organism in various ways: physical, mechanical and chemical. Input
must be converted from external physical to internal signals. Electromagnetic
energy in both the visible and the nonvisible portion of the spectrum reaches
the pineal through a well-described neural pathway. Other external factors with
cyclic variations seem to influence the pineal through less clearly understood
transduction mechanisms.

The pineal integrates the
transduced environmental signal information and generates its own signals.
Through the integrated production and release of various neurohormonal
substances, the pineal brings order to the apparent chaos of the disparate
signals it receives.

Although melatonin is most
important, the pineal produces other substances that have signal-transducing
effects. Once released, pineal hormones have effects on other biosynthetic
pathways, which then become important for signal transduction. Understanding
their effects is essential to understanding pineal physiology.

The effects of pineal signals
occur at the level of cells, organs and organism behaviour. Such effects result
in physiologic changes within the internal environment, which are themselves
mri signals to the pineal.

Environmental Stimuli

Electromagnetic Energy

The effects of electromagnetic
field interactions with biological systems are only beginning to be understood.
Both light and non visible electromagnetic energy decrease the conversion of
serotonin to melatonin. Although the mechanisms are incompletely described, the
alterations in melatonin production due to light appear to be the same as those
due to nonvisible electromagnetic field exposure.

Light has an effect on the level
of melatonin production and release as well as on the rhythm of this production
and release. In humans exposed to moderate and low light, there are differences
not only in the level of salivary melatonin but also in the duration of the
melatonin peak and time of offset.

The control of melatonin
synthesis by light gives the pineal its essential photoperiodicity. Light has
two different effects on the circadian rhythm of melatonin production and
release: it acutely suppresses melatonin output according to the wavelength of
light and the circadian phase and it entrains or phase-shifts the underlying cellular pacemaker. The pathways for these different but related
effects may have the same origin.

Light causes configurational and
chemical changes in the rods and cones of the retina. These changes are the
basis of transduction of light energy into neural signals, which can be passed
along neural pathways to the pineal. In addition, pineal cells themselves
have photoreceptor properties demonstrated by recordings of responses to light
stimulation of isolated pineal cells, which show electrical reactions to
illumination.

Static magnetic fields
consistently and reproducibly perturb circadian melatonin rhythm. The effects
are reflected in alterations in levels of cyclic adenosine monophosphate (cAMP),
N-acetyl­transferase (NAT) activity, hydroxyindole-O-methyltransferase (HIOMT)
activity, and pineal and blood melatonin concentrations, all of which are
decreased by magnetic field exposure. S-Hydroxytryptamine (serotonin) is
increased as a consequence of decreased melatonin synthesis.

Although the mechanisms for the
influence of nonvisible electromagnetic energy on melatonin formation are not
known, the retina is thought to be the magnetoreceptor. Alterations in the
retinal magnetoreceptor are transmitted to the suprachiasmatic nucleus.

Magnetic fields cause depression
of melatonin levels in experimental rats. The rat pineal also responds to
pulsed static magnetic fields with a decrease in NAT activity. Interestingly,
the effect occurs during the middle or late dark phase but not during the light
phase or early dark phase. The reason for differences in the response to magnetic field
during different portions of the photo­period is not known. In humans.
6-hydroxymelatonin excretion in urine is lower in users of magnetic
field-emitting as opposed to conventional electric blankets.

Temperature

Alterations in periods of sun
and seasonal temperature changes require homeostatic and behavioural adaptations
in warm-blooded animals. As coordinator of circadian seasonal responses, the
pineal can affect mechanisms of temperature change anticipation, detection and
response.

Elevation of temperature has
been shown to increase the amplitude of the melatonin rhythm in cultured chick
pineal cells. In a study in which melatonin levels were manipulated through
administration of a beta-adrenergic antagonist, there was an inverse
relationship between body core temperature and melatonin levels. The result
suggests a possible clinical use for melatonin in conditions associated with
loss of circadian body core temperature rhythm.

Other forms of high energy also
affect pineal activity. Whole body irradiation with 14.35-Gy gamma rays was
shown to increase pineal NAT activity in rats.

Input to the Pineal

The neural pathway through which
light influences the pineal originates at the retina. Axons of
certain retinal ganglion cells travel through the optic nerves, branching off to
form a separate pathway, the retinohypothalamic tract to the suprachiasmatic
nucleus (SCN). Some light information also reaches the SCN via the lateral geniculate body.

The biological clock appears to
be in the SCN, which has a high density of melatonin receptors to receive
mri from the pineal. Some melatonin receptors that mediate seasonal
reproductive behavioural changes are thought to reside in the anterior
pituitary gland (pars tuberalis).

Light activation of the retinal
ganglion cells inhibits the SCN, while it leaves the SCN active to stimulate the
next station of the pathway, the paraventricular nucleus. Innervation to the SCN
is bilateral, although predominantly from the contralateral retina. The
nucleus is better studied in lower animals, in whom it is better defined; in
humans it is more diffuse.

Efferent signals of the SCN are
not fully understood. Some appear to be neural (those to the hypothalamus in
particular), but some may occur through release of a diffusible substance into
the CSF.

Axons of paraventricular neurons
travel through the medial forebrain bundle to the intermediolateral area of the
upper thoracic spinal cord. The intermediolateral axons are the presynaptic
input to superior cervical ganglion cells, whose efferents travel initially with
other sympathetic fibers along the carotid artery; ultimately, however, they
form distinct fiber tracts, the bilateral nervi conarii, which synapse on pineal
cells.

The superior cervical ganglion
is the source of the postganglionic output to the pineal. Norepinephrine is
released from postganglionic fibers, primarily during darkness. In darkness,
the SCN is electrically inactive. In light the SCN is inhibited, which leads to
decreased norepinephrine release. The norepinephrine then stimulates beta1 receptors, which,
through induction of protein synthesis via the G protein-mediated cAMP second
messenger system, increase production of melatonin.

Sympathetic fiber endings do not
directly end on pinealocytes but rather are precapillary. The norepinephrine
they release, reaches the pineal cells by diffusion. Although sympathetic
innervation of the pineal has been proved only in lower species, cervical spine
injury is a model for sympathetic denervation in humans. Following high cervical
spinal cord injury, there is loss of the normal melatonin cycle and an increase
in 24-h production of the hormone. In addition, stages 3 and 4 and
rapid-eye-movement (REM) sleep, all of which can be induced experimentally by
melatonin administration, are disrupted by cord transection.

The neuroendocrine effects of
the superior cervical ganglion (SCG) can be demonstrated by ablation of the
ganglion, which results in changes in prolactin release, changes in drinking
behaviour, disruption of photoperiod reproductive control, and changes in
thyroid and oxytocin activity.

The SCG is an important
modulator at the pineal neuroeffector junction. Presynaptically, norepinephrine
influences alpha- and beta-adrenergic receptors. Postsynaptic substances from
the effector (pineal) cells, such as serotonin, provide mri on
presynaptic cells. Prostaglandin E2 exerts a negative influence on
transmission.

The innervation of the pineal is
probably almost exclusively sympathetic, although there is some evidence of
parasympathetic innervation in some lower mammals. Parasympathetic fibers
originate at the superior salivatory nucleus of the seventh cranial nerve,
travel along the greater superficial petrosal nerve, and reach the pineal
probably through the habenular and posterior commissures. The physiologic
significance of acetylcholinergic parasympathetic input to the pineal is
unknown.

Pineal substances are released
by ependymal secretion or direct release of products of the endoplasmic
reticulum after processing by the Golgi apparatus. This release, into
pericellular and pericapillary spaces, is under the control of the sympathetic
nervous system.

Immunohistochemical methods have
been used to determine that histaminergic nerve fibers, originating from the
posterior hypothalamus, project to the pineal complex of the rat. Histamine
must therefore be considered a putative neurotransmitter contained in the central innervation of
the pineal gland, but its function in pineal physiology has not been elucidated.

Although neural input of
transduced environmental signals is important in setting the biological clock,
pineal cells seem to have their own intrinsic rhythmicity, independent of
external signals. Chick pineal cells maintained in dissociated cell culture
express an intrinsic photosensitive circadian oscillator, whose mechanism is not
fully understood. A model with dissociated lizard pineal cells demonstrated
circadian rhythms of melatonin secretion, in the absence of neural or humoral
input. Blind humans with no retinas showed a slightly greater than 24-h cyclic
variability in melatonin levels.

Pineal Output: Substrates for
Pineal Effects

Melatonin

The neural pathways convey
information about environmental electromagnetic energy. At the pineal, this
information is transduced into physiologically effective signals through the
release of various chemical compounds. Although modern assay techniques have
detected numerous pineal products, the two most important groups are the indole
amines melatonin and serotonin, and pineal peptides.

Melatonin synthesis and release
follow a circadian rhythm with high nocturnal and low diurnal levels. Light of
varying intensity, wavelength, and duration of exposure, and darkness influence
melatonin production by affecting cAMP and norepinephrine control mechanisms.

Although influenced by cycles of
light and darkness, melatonin has its own intrinsic circadian rhythm. Lewy and
Newsome demonstrated cyclicity in melatonin levels in blind subjects.

Melatonin is only briefly stored
in the pinealocyte. Because of its high lipophilicity, it rapidly crosses cell
membranes and enters the blood stream and possibly the CSF, where levels of
melatonin are much lower than but parallel to those in blood. Cisternal
injection of melatonin leads to increases in hypothalamic cAMP. However, the
significance of melatonin in CSF is not known.

Melatonin was initially
described as a most potent substance in blanching amphibian melanocytes by
causing aggregation of intracellular melanin granules. It also antagonizes
the darkening effects of melanocyte-stimulating hormone.

Melatonin is a 232-dalton indole
amine (a seven-carbon two-ring structure with an attaching -NH2),
N-acetyl-5­methoxytryptamine, which is synthesized in pinealocytes (as well as
in the retina, red blood cells, hypothalamus, SCN, intestine and peripheral
nerves) from tryptophan. The existence of extrapineal sites has been
demonstrated in experiments in rats: loading with tryptophan caused increased
melatonin levels in pinealectomized animals as well as those with intact
glands.

Melatonin has a half-life of 10
to 40 min. In rats, 90 percent is cleared in one pass through the liver. In
mice, 70 to 80 percent is converted into inactive metabolites by liver microsomal systems.

Melatonin synthesis from
tryptophan is a two-stage process. After the circulating amino acid
is taken up from blood by pinealocytes, tryptophan is first converted to
serotonin by a hydroxylation step followed by a decarboxylation step. Serotonin
is then converted to melatonin by three steps in which a series of enzymes successively add an acetyl, methyl and finally a
hydroxyl group to the indole ring.

The rate-limiting step is the
conversion of serotonin to N-acetylserotonin by the enzyme
N-acetyltransferase (NAT), which is induced by darkness at the retina and
converts serotonin to melatonin. NAT activity has its own rhythmicity and can be
followed as a marker for melatonin. NAT activity decreases toward the end of
the dark phase, suggesting that some inactivating substance may influence the
enzyme. The next enzymatic reaction, conversion of N-acetyltryptophan to
melatonin, is catalyzed by hydroxyindole-O-methyltransferase (HIOMT). Induction
or suppression of this rate-limiting enzyme synthesis by cAMP is a potential
site of melatonin synthesis regulation.

Once melatonin is produced in
the pineal gland, it is quickly released into the vascular system. The rapid
release of melatonin is generally believed to relate to its high lipophilicity,
which allows it to pass readily through the membrane of the pinealocytes and the
endothelial cells that line the capillaries. In addition to melatonin, two
pineal peptides that can be used to follow melatonin effects are methoxytryptamine and methoxytryptophol.

Serotonin

Although melatonin is the most
important compound produced by the pineal, serotonin, an intermediate product in
the synthetic pathway, also displays periodicity and may itself be important as
a homeostatic agent or as part of some "biological clock" mechanism.

The concentration of serotonin
in the pineal is 250 times greater than that in any other region of the brain,
and the concentration is higher in the brain than anywhere else in the body. At
night the concentration is 10 to 20 mg/g of pineal tissue: during the day this
rises to 60 to 90 mg/g. It is postulated that less serotonin is secreted at
night because of its consumption as a precursor in melatonin synthesis.

Pineal Peptides

Several peptides are also
produced and released by the pineal and may participate in its functional
activity. Some of these are exclusive to the pineal, whereas others are found
elsewhere in the body. Several are putative neurotransmitters. It is extremely
difficult to isolate peptides because so many are present in the pineal, but
the number identified by immunocytochemical techniques continues to grow.

Many neuropeptides are produced
at sympathetic synaptic endings and released at the pineal: they include
vasopressin, oxytocin, somatostatin, α-melanocyte-stimulating hormone,
endorphin, vasoactive intestinal peptide (VIP), substance P, luteinizing
hormone-releasing hormone (LHRH), thyrotropin-releasing hormone, angiotensin
II, adrenocorticotropic hormone (ACTH), neurophysins I and II and
α-albumin
(which is identical to GFAP). These substances may be released into the synaptic
cleft or may enter the blood stream to act as hormones.

Several antigonadotropins were
the first pineal peptides to be isolated. They act on the hypothalamus,
affecting levels of prolactin, luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). Their mechanism of action seems to be an
effect on catecholamine turnover, specifically by increasing dopamine
synthesis.

The neurohypophyseal substances
vasopressin and oxytocin­like peptides have also been isolated from the pineal:
this has led to speculation of possible hypothalamic influences on pineal
activity. These substances are thought to reach the pineal via extrahypothalamic fibers whose cell bodies
are in the magnocellular portion of the hypothalamus. LHRH and VIP have also
been immunocytochemically demonstrated in the pineal.

Arginine vasotocin (AVT), a nonapeptide differing from arginine vasopressin in only one amino acid,
has been isolated from the pineal. AVT is found in lower animals and was initially
isolated from bovine pineals, although it is also produced in the pituitary.
In mammals it is produced by specialized pineal cells. AVT is thought to act
through the serotonin pathway by interfering with serotonin release at
postsynaptic receptor sites. It may also exert its effect through actions on the
GABA-containing habenuloraphe pathway. The substance has actions like those of
melatonin, but it is far more potent. It has sleep-inducing and anticonvulsant
effects and can induce changes in the EEG and promote REM sleep.

Recoverin is a 26-kDa protein that binds to calcium and activates guanylate cyclase
in retinal photoreceptors when, upon photoexcitation, the intracellular
concentration of free calcium drops. It is found only in photosensitive cells
and may be involved in photosignal transduction.

Pineal Action

Pineal transduction of physical
environmental signals is a function of the anatomic and chemical substrate of
the gland as well as of physiologic mechanisms for signal generation and
control. The anatomic location in relation to neural pathways,
neurotransmitters and the receptors that pass and receive signals along the
pathway, as well as the pathways for synthesis and release of hormonal
products, are all important in transduction. Control and mri mechanisms and
mechanisms by which the pineal hormones interact with target cells underlie
pineal's function as a link between an external environmental stimulus and
internal end organ (homeostatic) responses.

Mechanisms of Action

At the molecular level, one of
the proposed mechanisms of melatonin could be through binding to calmodulin.
Studies have demonstrated a specific melatonin-binding site. Interactions with
calmodulin would enable melatonin to participate in the modulation of many
intracellular functions dependent on Ca2+, which could include cytoskeletal
rearrangements and inhibition of calmodulin-dependent phosphodiesterase
activity. Phylogenetic preservation of calmodulin and melatonin may reflect the
participation of both in a fundamental
physiologic mechanism of cellular regulation and synchronization.

The cAMP system is important in
mediating the effects of the hormone. Prolonged melatonin exposure affects the
sensitivity of the cAMP system and increases the production of cAMP. Melatonin
also increases the sensitivity of the cAMP system to stimulation by substances
such as forskolin through a mechanism not dependent on new protein synthesis.

Because of the high
lipophilicity of the melatonin molecule, Reiter postulates that the most
important mechanisms of melatonin action may occur not at the cell membrane but
rather within the cell. He recently reviewed evidence that melatonin interacts
with oxygen-centered free radicals, reducing their number by two mechanisms:
stimulation of glutathione peroxidase, which breaks down hydroxyl radical and
scavenging by the melatonin molecule itself, of free radicals. Melatonin binds
within the nucleus, where it may have a role as protector of nearby DNA.

Melatonin action may be mediated
through an effect on the microtubules, which are intracellular protein
structures important in cellular movement, division and axon transport. There
is evidence that melatonin causes ultrastructural changes in microtubules. An
effect on microtubules like that of colchicine has been seen when the structures
are allowed to recover following disruption by temperature elevation.

Melatonin causes a decrease in
the protein content of hypothalamic microtubules. It has been shown to
decrease axoplasmic transport in the sciatic and optic nerves.

The microtubule hypothesis for
the action of melatonin is attractive because it provides a mechanism for
melanin granule aggregation in melanocytes and consequent skin lightening.
Aggregation of granules requires participation of microtubules.

The microtubule hypothesis has
been challenged by investigators who administered melatonin to chick embryos
and noted no changes in the central nervous system. Other mechanisms for melatonin action haw been
postulated, including effects on cellular cyclic guanosine 3.5' -monophosphate
(cGMP) and prostaglandins.

Melatonin has been found in the
hypothalamus, midbrain, pituitary, peripheral nerves and gonads. Steroid
receptors are found on pineal cells and it is postulated that melatonin may
alter the number or affect intracellular processing of steroid-receptor
complexes at that site. The physiologic significance of melatonin binding in
multiple tissues is in many cases unknown. [125I] iodomelatonin
binds with high specificity at several sites in the chicken spinal cord with diurnal
variation. Although this suggests a direct melatonin effect on the cord, the
actual significance of these binding sites is unknown.

Melatonin receptors are found
in many organs throughout the body. In cardiac muscle, melatonin induces changes
in calcium and magnesium ion-dependent
ATPase activity. The presence of putative melatonin receptors in the guinea
pig kidney supports hypotheses of melatonin-regulated renin secretion together
with renal excretory functions via melatonin receptors. In many locations,
the function of the pineal hormone remains unknown.

Control of and mri to the
Pineal

Pineal activity can be
controlled by affecting either the intrinsic cyclicity of pineal cells or by
affecting rates of production and release of pineal products. Mechanisms by
which intrinsic cellular rhythms would be reprogrammed remain to be worked out.
Production and release of pineal products can be influenced at a genetic,
enzymatic, or neural level. Although both show circadian oscillations, chick
retina and pineal have slightly different NAT activity and melatonin content
responses to constant light and darkness.

Reprogramming Cycles and
Rhythmicity: Levels of melatonin can be regulated at many points along the
synthetic and release pathways. Neurotransmitters, genes, and enzymes each
have their own synthetic and production control pathways that affect
melatonin production and release.

Factors known to influence
melatonin level (besides electromagnetic radiation) include age, body
weight and height, use of glasses, beta blockers, chlorpromazine,
antidepressants and genetic variations. Melatonin production and release
are affected by the change of seasons, phases of the menstrual cycle,
puberty and aging.

Hormones such as
testosterone, progesterone, prolactin, thyroxine, FSH, LH, and parathyroid
hormone have all been shown to influence pineal activity as measured by the
level of melatonin synthesis within the gland. They exert their effects
either directly on pinealocytes or indirectly on sympathetic nerves in the
pineal. Receptors for many hormones have been detected on pineal cells.

Genetic Control: The locus
controlling pineal serotonin NAT has recently been localized
to mouse chromosome 11. Studies of induction of messenger RNA (mRNA)
transcription and other genetic changes will be important in the future
definition of melatonin production and release control mechanisms. Protooncogenes
may participate. Stressful stimuli induce a significant increase in the
expression of c-fos mRNA in the pineal gland suggesting a possible
mechanism by which such stimuli could influence pineal function.

Enzymatic Influences: Any
factor that influences protein synthesis can potentially enhance or blunt
melatonin's effects or even establish new cycles within the larger one
regulated by light and darkness. Enzyme levels are determined by rates of
protein synthesis but also by inhibitory and excitatory substances that may
operate on NAT in the pineal. Alteration in receptor number
and sensitivity is yet another mechanism by which cyclicity could be
influenced.

The list of substances
produced by the pineal all of which have their own control mechanisms
susceptible to cyclic influences, includes such biologically active agents
as tryptophan, histamine, and angiotensin I. Target tissue sensitivity to
melatonin varies with the number and sensitivity of receptors there and the
influence of other hormones. All these target tissue-resident factors are
amenable to cyclic influences. A system of interacting regulating
influences enables the organism to respond to a plethora of periodically
variable challenges, of which light is just one.

Understanding the control of
pineal melatonin production and release requires measurement of levels of
melatonin and intermediate substances in its production pathway (such as
serotonin) as well as activities of the various enzymes (adenyl cyclase,
HIOMT, NAT) participating in its synthesis. The level of NAT is of special
importance because this enzyme catalyzes the rate-limiting reaction in the
synthetic pathway, the conversion of serotonin to melatonin. Its activity
increases in darkness. Serotonin N-acetyltrans­ferase (SNAT) is truly
circadian (i.e., not dependent on light).

With the onset of darkness
there is an increase in the firing rate of sympathetic neurons
with endings on pineal cells. A large increase in pineal NAT
activity is associated with increased local turnover of norepinephrine and
the pineal takes up circulating dietary phenylalanine.

Electrical activity in the
suprachiasmatic nucleus (and thus stimulation of norepinephrine release and
ultimately of melatonin production and release) is shut off within 1s of
exposure of the retina to light. The degree to which this activity is
curtailed depends on the intensity of the light to which the retina is
exposed, Light wavelength may be important in suppressing melatonin
production. Blue light (wavelength of 500 to 520 nm) seems to be most
effective and suggests that rhodopsin is an important participant in the
effect.

Additional control is
possible along the synthetic pathways of the substances that affect the
melatonin pathway, the most important being norepinephrine, Phenylalanine
is first converted to tyrosine, Tyrosine. in a rate-limiting step catalyzed
by tyrosine hydroxylase is converted to 3,4-dihydroxyphenylalanine (DOPA).
This reaction occurs 50 percent faster at night. DOPA is then converted to
dopamine by DOPA decarboxylase. Finally, dopamine is converted to
norepinephrine. This multienzymatic biosynthetic process is stimulated by
darkness. The norepinephrine is then released, crosses through the synaptic
space, and stimulates production and release of melatonin by pineal cells.
Norepinephrine is deactivated by the well-described mechanisms of
diffusion, reuptake and enzymatic degradation by monoamine oxidase and
catechol-O-methyItransferase.

Levels of NAT, the enzyme
that adds an -OCH3 to serotonin in the melatonin synthetic pathway, have
been shown to increase following beta-adrenergic activation of cAMP activity
at night. In light, NAT activity decreases. The enzyme may be regulated by a
disulfide peptide, such as arginine vasopressin, somatomedin, or insulin in
light, but the functional (teleological) significance of this is unclear.

Long-term ethanol
administration has been shown to result in a significant decrease in NAT
activity in the pineal. The significance of this finding is unclear.

NAT activity is variable
during the light-dark cycle. Increases in the NAT conversion reaction
require increases in NAT itself, which requires protein and therefore mRNA
synthesis. These processes account for the time lag noted from onset of
darkness to increase in melatonin level.

Data show that melatonin
applied in the late light period advances the evening NAT rise during a
short photoperiod only; during a longer photoperiod, the phase-advancing
effect of melatonin may conflict with a phase-delaying effect of the end of
a light period, and the effect of light exposure overrides that of
melatonin.

Rhythmic control of
melatonin production by modulation of NAT activity is mediated through
activity of cAMP. cAMP is important for protein synthesis and maintenance
of NAT in active form. cAMP concentration is higher in the pineal than in
any other part of the brain. cAMP is a regulator of pineal melatonin
production in the chick as evidenced by the fact that chemicals that raise
cAMP (or analogue) levels also raise melatonin levels. Substances that lower
cAMP lower melatonin. There is also a circadian pacemaker in pineal cells
that regulates melatonin production independent of cAMP.

In the chick pineal, cAMP
appears to act downstream in the pathway that generates circadian rhythm. In
experiments in which chemicals were added to raise cAMP to supersaturated
levels, there was no continuous elevation of melatonin level. Rather, the
cyclic rise and fall of melatonin continued. This indicates that the
melatonin pacemaker is not cAMP. cAMP and the pacemaker act synergistically to
regulate SNAT activity and the melatonin rhythm, with cAMP mediating acute
effects and amplitude regulation.

Not surprisingly, rhodopson and
retinoid activity in the retina is coordinated with activity of NAT and
melatonin production. HIOMT catalyzes another step in the melatonin synthetic
pathway and thus is a site for potential metabolic control. In rats, HIOMT peak
enzyme activity occurs 5 h after the onset of darkness and is followed by two
lesser bursts of activity preceding each change in the photoperiod. There is an
approximately 18-fold increase in methylating capacity at night.

Neural Influences on Production
and Release of Pineal Products

Beta-adrenergic receptors:
Neurotransmitter receptors are an important site for
control and modulation of pineal activity by the nervous system. Beta-adrenergic
receptors are located outside of the blood-brain barrier, which supports the
view of the pineal as a peripheral, rather than a central organ. Postganglionic
cells from the superior cervical ganglion release norepinephrine: norepinephrine
binds to beta1-adrenergic receptors on pinealocytes. which stimulate
production of cAMP through a G protein­mediated mechanism. The increase in cAMP
increases mRNA production, specifically of NAT.

The number of beta-adrenergic
receptors increases at the end of the light period. At night, release of
norepinephrine from terminals leads to a decrease in the number of receptors by
the end of the dark phase. NAT activity increases further if the beta1 agonist
isoproterenol is given at the end of the light phase. when receptors are more
abundant, than if given at the end of the dark phase, when they are fewer. There
is a great fluctuation in the level of beta-adrenergic receptors over 24 h.

The number of postsynaptic
receptors can be increased by increasing the length of an animal's exposure to
light or by surgically removing the cervical ganglion. Under such conditions
the number of receptors on pineal cells increases and there is supersensitivity to adrenergic agents. Administration of isoproterenol is not
associated with an increase in circulating melatonin in humans; perhaps some
coneurotransmitter is required that is not stimulated by isoproterenol (e.g.,
GABA, histamine, DOPA). Administration of beta blockers blocks the night-time
increase in pineal melatonin (alpha blockers have no effect).

Alpha-adrenergic receptors:
Alpha-adrenergic receptors have not yet been identified in humans. In rats,
alpha-adrenergic receptors of the pineal may be related to the regulation of phospholipid metabolism.

The activity of rat
alpha-adrenergic receptors seems to be prostaglandin-mediated. Norepinephrine
stimulates pineal production of prostaglandins and phosphatidyl inositol. The
prostaglandin­mediated change in the cell membrane and its components may be
part of a neuroendocrine mechanism for signal transduction.

Alpha-adrenergic receptors that
may respond to substances released by presynaptic axons whose neuronal cell
bodies are located centrally in the brain are also present on pinealocytes.
Stimulation of these is thought to induce changes in the phosphatidyl inositol
pathway.

Adrenergic mechanisms of control:
Adrenergic stimulation of the adult pineal gland increases cAMP and cGMP
production by over 100-fold. Beta-adrenergic stimulation results in an
increase in alpha-mediated cyclase activation, which is potentiated by alpha1-adrenergic-induced increases in intracellular calcium (Ca2+) and
calcium-dependent protein kinase. Alpha-adrenergic receptors have a greater
effect on the pineal during the course of development, whereas beta-adrenergic
receptors are most important in the adult.

cAMP appears shortly after
birth, cGMP after the second week of life. In a study that raised levels of
intracellular calcium, cGMP did not appear until after the second week of life.
However, if cells from before the second week were placed in same medium as
cells from after second week, they would begin to make cGMP, suggesting the
presence of a diffusible factor.

GABA-ergic receptors: Fifteen
percent of pinealocytes are positive for GABA. Glutamic acid decarboxylase is
found in the pineal gland as well as the GABA receptor complex, which includes
the GABA-binding site, the benzodiazepine-binding site, and the chloride ionophore, GABA receptor-positive pinealocytes have neuron-like properties in
that they release GABA in response to depolarizing stimuli. In the rat pineal,
GABA is released following interaction of norepinephrine with alpha1
adrenoreceptors. Both A and B types of GABA receptors have been described in
the pineal. Activation of A receptors interferes with norepinephrine­induced
melatonin release. Activation of B receptors decreases norepinephrine
release. Presynaptically, GABA increases maximal velocity but decreases the affinity of
norepinephrine uptake. The pre- and postsynaptic effects of GABA in the pineal
seem to be similar to those in other parts of the brain.

A relationship between
melatonin and cortical benzodiazepine receptors is evidenced by the fact that
melatonin administration maintains the concentration of cortical benzodiazepine
receptors in pinealectomized and superior cervical ganglionectomized rats. Nicotine
diminishes norepinephrine-stimulated melatonin accumulation, although it has no
effect on melatonin production or release. A binding site for the excitatory
neurotransmitter glutamate has recently been identified and characterized in
the rat pineal. Glutamate may play a modulating role in pineal physiology.

Suprachiasmatic nucleus:
Regulation of the suprachiasmatic biological clock is not fully understood.
Administration of the pineal hormone melatonin to rats induces expression of Fos,
the protein product of the c-fos proto-oncogene in the SCN. c-fos is activated
only if the melatonin is given during the late phase of subjective day. Because
melatonin administration late in the day advances the SCN biological clock, it
must do so through a mechanism independent of c-fos.

Melatonin-receptor density in
the rat in both the pars tuberalis and SCN increases in pinealectomized animals
as well as those exposed to light. Administration of melatonin reverses this
effect, indicating that melatonin itself regulates receptor density in these
areas.

Melatonin-receptor levels are
highly variable throughout the light-dark cycle. It is believed that receptor
down-regulation may account for some of the different effects of the hormone at
different phases in the cycle.

Ovarian hormones inhibit rat
pineal melatonin production in the proestrous night. RU486 fails to block this
effect, which suggests that estradiol is its mediator.

Pineal cells express a 3.5-kb
mRNA that corresponds to the estradiol-17 beta receptor. At low concentrations,
administered estradiol is inhibitory: at high concentrations it is stimulatory.
These effects were modified, depending on when during the light­dark cycle the
estradiol was administered.

Elevated levels of melatonin were found in association with
pituitary tumors secreting either prolactin or growth hormone.

Effects on neural cells of
melatonin: The effects of melatonin have been most studied in the hypothalamus.
Melatonin has been shown to change protein synthesis, GABA content and
neurohormone release, and to decrease cAMP accumulation as well as to alter
excitatory responses. Melatonin has effects on neuronal activity and protein
synthesis in several brain locations, including the hypothalamus, midbrain and
pineal.

Melatonin and vasotocin have
effects on spontaneous neuronal activity in certain areas of the brain. The
effects of microiontophoretic application of melatonin and melatonin plus
vasotocin on spontaneously active neurons of the caudate-putamen in
sham­operated and pinealectomized rats were studied. Administration of
melatonin alone to caudate-putamen cells caused inhibition of approximately
three-quarters of neurons. Melatonin combined with vasotocin (another prominent
pineal product) increased inhibition to 100 percent.

Ethanol Levels and Consumption,
and Melatonin Production: Ethanol at usually consumed levels was shown to inhibit
melatonin production in healthy volunteers. There was an associated increase
in noradrenergic activity. The combined effects may be associated with
disturbances of sleep and performance observed with this substance.

End-Organ Response

The pineal has been
postulated to play a role in various other conditions, such as glaucoma, porphyria, hemochromatosis and endocrine disorders. Myelin formation and maintenance can
be altered following pinealectomy: this is thought to be due to alterations in
levels of long-chain fatty acids.

Endocrine effects of the pineal
include influences on the thyroid and adrenals. The pineal has been
demonstrated to have effects on growth, body temperature, blood pressure, motor
activity and sleep. The effects of melatonin differ, depending on the point in
the photoperiod at which it is given.

Calcium Binding

Melatonin binds to calmodulin
with high affinity. This enables it to influence cellular activity within
physiologic ranges. It may be through its interaction with calmodulin that
melatonin affects many cellular rhythmic activities. Melatonin and calmodulin
are both phylogenetically well-preserved molecules, which suggests that their
interaction represents a primary mechanism for regulation and synchronization
of cellular physiology.

Studies in rats have shown that
pinealectomy induces hypertension that can be blocked by melatonin
administration. This effect is thought to be related to stimulation of the
renin-angiotensin system or perhaps to stimulation of central adrenergic
receptors. Weight and volume of the pineal have been shown to be higher in aging hypertensives than in normotensives. Altered pineal sensitivity to
norepinephrine and isoproterenol has been demonstrated in spontaneously
hypertensive rats and is thought to be related to stimulation of PKC and
intracellular calcium.

Melatonin receptors are far more
prevalent across cell types than had previously been suspected before
radiolabeling assays were available. Although binding studies are a means of
determining potential sites of melatonin action, their detection does not
necessarily indicate the mechanism of action.

Binding of melatonin has been
demonstrated in the anteroventral and anterodorsal nuclei of the rat, which
suggests that some of the effects of melatonin are mediated via the limbic
thalamus. These effects are thought to be due to interaction with specific,
high-affinity melatonin receptors in the SCN and hypophyseal pars tuberalis,
respectively. Receptor localization studies using 125I have shown melatonin
receptors in the SCN and pars tuberalis of seasonally breeding species,
including the rhesus monkey. The pars tuberalis receptors are absent in humans.

Melatonin mri onto SCN

Several studies have indicated
that pineal melatonin feeds back on SCN rhythmicity to modulate circadian
patterns of activity and other processes. However, the nature and system-level
significance of this mri are unknown. Recently published work indicates
that although pinealectomy does not affect rat circadian rhythms in light-dark
cycles or constant darkness, wheel-running activity rhythms are severely
disrupted in constant light. These data suggest either that pineal mri
regulates the light sensitivity of the SCN or that it affects coupling among
circadian oscillators within the SCN or between the SCN and its output.

Pineal (Melatonin) Influences on
Hormones

Melatonin influences activity
of many hormones and is, in turn, influences by them through mri
mechanisms. The interaction of melatonin and prolactin is of particular interest
because it implicates several potential subsidiary control systems. Bright
light at night leads to decreased prolactin levels paralleling those of
melatonin.

Melatonin's effect on prolactin
could be mediated through an effect on the SCN. perhaps mediated through an
effect on the dopamine or endogenous opioid system. Total levels of prolactin
secretion remained constant in light exposure experiments, which suggests that
modulation occurs at the level of secretion rather than production. The
interaction with prolactin may be part of the mechanism for melatonin to
influence the reproductive system.

Studies in pinealectomized rats
demonstrated a greater ACTH response to stress. This suggests that the pineal
may suppress stress-reactive ACTH outflow.

There is a relationship between
melatonin and the adrenal cortex that is dissociated from the
hypothalamic-pituitary-adrenal axis. Administration of melatonin leads to an
increase in adrenal corticosteroid levels.

Pineal influence over the
neurohypophysis has been shown in experiments on pinealectomized animals.
Exposure to constant light, while altering the patterns of neurohypophyseal
activity in the pineal intact group, had little effect on the pinealectomized
animals, indicating that the effect of light is mediated by the pineal.

Serotonergic System

Melatonin probably also acts
through effects on the serotonergic system, which has an intrinsic component in
the parvocellular nuclei of the hypothalamus as well as the system of raphe
nuclear projections to the hypothalamus via the median forebrain bundle.
Melatonin is not a competitive binder to serotonin receptors and therefore exerts its effect on
cells of the serotonergic system by separate receptors. Melatonin and serotonin
have antigonadotropic effects. The effect of melatonin on serotonin metabolism
is controversial. Electrical stimulation of the pineal produces hypertension
and tachycardia in the rat antagonized by serotonin receptor antagonism,
bilateral vagotomy or spinal transection.

Immune System

The emerging link between the
immune system and the pineal may reflect an evolutionary connection between
reproduction and recognition of self. Melatonin has an immunostimulatory
effect, especially in states of immunodepression, including that induced by
stress. The immune system link with melatonin suggests its possible use as a
therapeutic agent in immunodeficiency as well as in cancer immunotherapy.

A principal target of melatonin
is the thymus. The immunoenhancing effect seems to be due to T-helper
cell-derived opioid peptides and lymphokines. Pituitary hormones may also be
involved. Induction of these lymphokines by melatonin suggests the presence of
specific binding sites on immune system cells. Melatonin production by the
pineal is modulated by interleukin-2 (lL-2) and thymic hormones. The pineal
gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine
network which functions as an unconscious, diffuse sensory organ.
Administration of exogenous melatonin significantly enhances murine
antibody-dependent cytotoxicity, whereas pinealectomy impairs it.

The presence of melatonin
receptors on cells of the immune system does not necessarily implicate the
pineal hormone as an immune regulator; however, a
study on binding of 2­[125]iodomelatonin to human
lymphocytes discovered that there were two types of receptors, differentiated by
both the affinity of binding and the second messenger stimulated by binding.
This is suggestive of a complex stimulation and regulatory mechanism.

Another study on diurnal rhythms
of chick serum and granulocyte lysozyme found that rhythmicity abolished after
pinealectomy could be restored by administering melatonin to the animals. This
suggests that melatonin may have an influence on nonspecific immune mechanisms.
Melatonin may be associated with multiple sclerosis through its effects on
biological cycles and the immune system.

A study of IL-2 combined with
melatonin in patients with solid neoplasms found a significant
increase in the mean number of lymphocytes. This effect was not observed with
melatonin alone, which suggests that IL-2 must be present for this immunostimulatory effect of melatonin to occur.

Neoplasia

Melatonin promotes the growth of
certain tumors. Although not itself known to be carcinogenic, the pineal
hormone, acting through receptors linked to the cAMP and G protein second
messenger systems, may participate in regulatory processes that become altered
in preneoplastic states. Thus melatonin may act as an inductive factor where
permissive intracellular conditions exist.

Pineal gland hyperplasia and
elevated levels of melatonin have been demonstrated in association with
disseminated melanoma. Melatonin receptors have been detected on certain types
of breast tumor cells. There is an inverse relationship between melatonin level
and level of estrogen receptors in patients with breast cancer.

An association between human
breast cancer and levels of melatonin is suggested by the finding of depressed
melatonin levels in the serum of patients with primary breast cancer.
Experimental breast cancer cells have been successfully inhibited by melatonin,
which suggests the possibility of using melatonin and other pineal­derived
substances as antineoplastics.

Levels of melatonin (but not
those of prolactin and growth hormone) in 132 cancer patients were
significantly higher than in 58 controls. Higher melatonin
levels seemed to correlate with the stage of cancer. Interesting in the
melatonin-neoplasia link is that levels of melatonin do not seem to be affected
by surgical removal and that the rhythmicity of melatonin secretion is
comparable to that in normals.

Several studies of the effect of
melatonin on different tumor types have found it to be largely inhibitory. The
mechanisms of this effect have been postulated to be mediated by effects on
mitotic activity: immunocompetence, or secretion of growth hormone,
somatomedin, ACTH or catecholamines. In one study, pinealectomy increased
the growth of transplanted tumor cells in hamsters, whereas melatonin reversed
this effect.

A study of tumor (erythroleukemia)
cells in culture looked at the inhibition of cellular proliferation by pineal
gland extracts. The gland had the most inhibitory activity in summer, whereas it
was only weakly inhibitory or even excitatory in winter. This suggests
seasonality of cancer occurrence.

Possible links between the
pineal and neoplasia are being investigated intensively. Understanding the
mechanisms whereby the pineal would induce or
inhibit neoplasia might shed light onto the process of neoplastic
transformation. Melatonin or another pineal substance could serve as a marker
for neoplastic induction or progression.

Effects on the rhythmicity of
melatonin secretion have been observed in cancer patients with breast,
prostate and other neoplasms. The pineals of patients with cancer have been
shown to be enlarged and degenerated, compared with age-matched controls.

Although an experimental model
does not exist, numerous physiologic and epidemiologic factors are consistent
with involvement of the pineal gland in the pathogenesis of endometrial
carcinoma.

Pinealectomy inhibited
leukemogenesis in a murine model, whereas melatonin promoted it. The melatonin
appeared to work through an opioid mediator as an opioid antagonist blocked the melatonin effect.

Growth and Development

Puberty

Mass lesions of the pineal
region are associated with precocious puberty. However, the role of the pineal
in puberty is still unclear. Melatonin levels are highest in both sexes between
ages 1 and 5 and then decrease until the end of puberty. Melatonin levels
have been shown to be the same for prepubertal and adult males as well as those
undergoing precocious puberty. A study that measured melatonin levels in
relation to stages of adrenarche found no relationship, indicating that
pineal-puberty relationships are not mediated through an effect of melatonin on
adrenarche.

A study of 57 normal children and 39 with disorders of onset
of puberty found no correlation between nocturnal peak melatonin levels and
those of testosterone, estradiol, or LH. This suggests that melatonin does not
have a major inhibitory effect on the hypothalamic-pituitary-gonadal axis
during childhood.

Evidence from other species, as
well as the association between melatonin and dysmenorrhoea, gonadal growth and
involution and reproduction. suggests a probable link between the pineal
hormone and puberty. This remains to be fully elucidated by current
experimental techniques.

The reason for the frequently
observed association between pineal neoplasms and precocious puberty is not
understood. Postulated mechanisms, other than an effect of melatonin, include
the tumour's secretion of unknown substances that induce pubertal changes.
Another possibility is modification of normal hormonal regulation mechanisms by
pressure or by mechanical effects of a pineal region mass on nearby brain
structures (such as the hypothalamus).

Reproduction

Pineal peptides and indoles seem
to affect fertility by restricting reproductive function to an optimal time of
the year, which improves survival of the species. The pineal converts photic
and temperature cues into meaningful messages by which reproduction and
nurturing are optimally timed.

The pineal effect on regulation
of reproductive activity is mediated by melatonin levels, which increase and
decrease during the lengthening and shortening of day-night periods as the
seasons change. When days are longer, the period of melatonin production is
prolonged, which may signal a season change to the animal, which could be a
factor in controlling reproductive activity.

In many animals, maturation of
the female reproductive organs is inhibited by the action of melatonin. During
the reproductive phase, melatonin has important coordinating roles in
regulating the timing of the LH surge and the production of progesterone. In
1963 Wurtman et al. first reported that melatonin given to female rats
decreased ovarian weight and increased the frequency of estrus. This antigonadotropic
effect has since been substantiated and may partly explain the effect of tumors
that ablate the pineal: a positive gonadotropic effect and, frequently,
precocious puberty.

After the identification of
melatonin and the determination of its relationship to photoperiodicity, the
most significant discovery about the hormone was of its effect on the
reproductive organs and their function in mammals. Recent studies have confirmed
that melatonin has effects on hypertrophy and atrophy of reproductive organs
(e.g., ovaries) in experimental animals.

Ultrastructural changes in
pineal cells have been observed in animals during different phases of the
breeding cycle. There is a decline in levels of circulating melatonin with
aging, suggesting that this chemical may be involved in the process of
menopause. Increases in enzyme and cellular organelle activity during gestation
have been documented.

The mediator of antigonadotropic activity of pineal extracts is unknown. Experiments with pineal
extracts containing no melatonin or steroid fractions showed potent antigonadotropic effects in an ovine model. implicating an "inhibin-like"
factor.

The pineal. presumably through
melatonin, controls the timing of the LH surge, The LH surge in pinealectomized
rats is variable. Administration of melatonin to pinealectomized animals shortly after a light-to-dark transition
improved regulation of the timing of the LH surge. Administration of melatonin
at other times in the light-dark cycle was ineffective. This shows that time of
administration with respect to the light-dark cycle is important to melatonin
effect.

Pineal effects on the menstrual
cycle are probably mediated through effects on the pineal centres that produce
and secrete gonadotropin-releasing hormone
(GnRH) and other reproduction­related hormones. The GnRH pulse generator can
be inactivated by melatonin. Melatonin release is increased during the dark
phase, which is longer during winter. Humans are not seasonal breeders, perhaps
because of a defect in the retinopineal pathway. Melatonin, if it can be
administered in a way that mimics the night-time amplitude and duration of
long-day breeders, might be an effective contraceptive.

In one study, short
photoperiods associated with increases in melatonin were associated in hamsters
with loss of estrus. This could be restored by pinealectomy. Melatonin
production and secretion patterns were altered in six studied
amenorrheic women, reflecting a probable link between the pituitary-gonadal
axis and the pineal.

Melatonin has been shown to
decrease the release of GnRH in castrated animals (minks) but not in uncastrated
controls. This implies that melatonin effects require testosterone mri.
Melatonin will cause testicular regression in pinealectomized hamsters only if
delivered in a specific temporal pattern.

Exposure of hamster seminiferous
tubule cells to melatonin caused regression and necrosis with increased
incidence of aspermic tubules. This effect is absent if a much larger dose of
melatonin is given over a prolonged period of time.

Melatonin levels in human milk
exhibit a daily rhythm of high levels at night and undetectable levels during
the day. These variations may communicate time-of-day information to
breast-fed infants.

Melatonin may affect the
behavioural as well as physiological aspects of reproduction, By using regulated.
timed infusion of mel­atonin. it is possible to show which secretory profile is
optimal to elicit certain seasonally appropriate behavioural and physiologic
reproductive responses. In hamsters and sheep the duration of the melatonin
infusion seems to be the crucial aspect of the signal.

Aging

The pineal is thought to be
active in all stages of human life. The gland maintains its weight and ability
to produce enzymes into the eighth decade. Circadian rhythms of pineal
excretion are not affected by aging or senile dementia. However 24-h mean
melatonin levels are half as great in the elderly as in the young. Melatonin
levels in the CSF also decrease with age. Several reasons for these decreases
have been suggested, including (1) changes in the release of the hormone, (2) an
increase in its metabolism or excretion. (3) an increased sensitivity to light
in the aged or (4) decreased or nonresponsive pineal beta-adrenergic
receptors.

Melatonin and serotonin may be
involved in the development of ischemic heart disease, Alzheimer's disease,
tumor formation and other degenerative processes associated with aging. The
favourable effects of dietary restriction on aging may also be related to
melatonin.

Excitatory amino acids inhibit
melatonin release. Melatonin is a potent nonenzymatic free
radical scavenger. Increased release of excitatory amino acids may account for
some of the effects of aging. The possible use of melatonin to slow down aging
is supported by experiments demonstrating decreased hydroxyl radical­induced
oxidative damage in experimental rats.

Oral administration of melatonin
to aging mice prolongs survival and preserves a youthful state. In one study,
pineal glands were grafted from young mice to older mice thymuses. Thymus tissue
remained youthful and T-cell function was preserved. (A diurnal rhythm in the
activity of superoxide dismutase has been observed, the significance of which is
not known.) Changes in the nightly melatonin peak provide a signal that
informs the organism of its age. It has been hypothesized that this "durational signal" at the cellular level is the sleep-induced pCO2 changes in
the blood.

Calcium availability is
decreased in aging and is postulated to be the cause of decreased beta- and
alpha-adrenergic responses leading to melatonin biosynthesis. A decreased
response of short sympathetic neurons to applied melatonin has been
demonstrated in rats. Increasing evidence that melatonin administered to rats
slows the rate of aging has led to the proposed use of melatonin to inhibit
aging due to free radicals.

Behavioural Effects

Any discussion of melatonin's
influences on human behavioural physiology must specify which effects result from
direct administration of purified melatonin and which result from whole gland
extract. In addition, many physiologic probabilities in animals are downgraded
to mere possibilities in humans, pending confirmatory human investigation.

The actions of the pineal (and
of melatonin) can be divided into two broad categories: behavioural and
nonbehavioural. Behavioural effects include regulation and synchronization of
biological activity into optimal cycles, such as for waking and sleeping, food
seeking and reproduction. This activity is often tied to environmental light
and dark variation, but there are intrinsic cycles as well. Persistence of locomotor circadian
rhythms in the face of functional pinealectomy induced by bright
light suggests the existence of a mechanism or mechanisms for cyclicity
independent of the pineal. An interesting proposed behavioural link is that
between melatonin-mediated changes in intracellular Ca2+ and infant colic.

Movement

A high dose of melatonin can
produce ataxia, incoordination, muscle relaxation, ptosis, piloerection, muscle
relaxation, extremity vasodilatation, and generalized decrease in movement. At
very high doses, flexor reflexes are impaired, breathing becomes laboured, and
body temperature decreases prior to death. Based on these findings, it has
been postulated that melatonin plays a role in movement and therefore in
movement disorders.

Studies of melatonin interaction
with L-dopa in rats and detection of the hormone in the substantia nigra
suggest a possible link to Parkinson's disease. Chronic oral melatonin
administration ameliorates Parkinsonian tremor and rigidity.

A link between melatonin and
amyotrophic lateral sclerosis (ALS) has also been proposed,
based on the observed influences of melatonin on axonal transport in sciatic and
other nerves. Melatonin is associated with the serotonergic transmission
systems, and serotonin is believed to be involved in the pathogenesis of ALS.

Treatment with L-dopa is
associated with dyskinesias thought to be due to striatal dopaminergic activity
perturbations. In laboratory animals, the pineal hormone melatonin has been
shown to regulate striatal dopaminergic activity and block L-dopa-induced
dyskinesias. Sandyk et al. report a dramatic improvement in L-dopa-induced
dyskinesias in a patient with Parkinson's disease treated with the application
of external magnetic fields.

Both heat and cold increase
locomotor activity in rats through a mechanism mediated by the pineal.
Pinealectomy attenuates the response. It is thought that these and other non
photic stimuli create stress from which pineal hormones promote escape through
increased motor activity.

Wheel-running activity in
hamsters is one of the experimental models used in correlating plasma melatonin
levels with locomotor activity. Complex circadian melatonin rhythms have been
associated with wheel-running activity.

Sleep- Wake Cycle and Epilepsy

Alpha rhythm appears around the
time of puberty in the human brain. Thus it is a marker for
psychosexual development, which is importantly influenced by the pineal.
Administration of melatonin blocks alpha rhythm, which suggests that melatonin's
progressive decline during childhood may enable the maturation of alpha rhythm. Sandyk proposes using alpha rhythm as a "neurophysiological marker" of pineal
activity in disorders associated with alpha rhythm disturbances, such as autism.
dyslexia, personality disorders, epilepsy, Tourette's syndrome and
schizophrenia.

Melatonin may act through a
thermoregulatory mechanism by lowering core body temperature and thereby
increasing sleep propensity. Melatonin has circadian cycling and hypnotic
effects, which make it a good candidate as an adjuvant drug for sleep in
conjunction with other drugs known to alter melatonin production, such as
beta-blockers and benzodiazepines.

Developmental periods associated
with increased melatonin are associated with decreased REM sleep: those with low
melatonin are associated with increased REM sleep. Sandyk proposes that low
melatonin is permissive for REM sleep. He further suggests that narcolepsy may
be due to a maturational defect of the pineal gland in infancy.

Melatonin is important for
maintaining sleep-wake cycles, and its absence or excess can cause
irregularities in REM sleep. Melatonin has been shown to induce sleep and
characteristic EEG rhythms in several species. Following intraperitoneal
administration of melatonin, brain stem serotonin has increased, which is
associated with sleep induction. In the elderly, decreased sleep is associated
with decreased melatonin levels. Intensive research is under way to investigate
the therapeutic use of melatonin or an analogue for patients with insomnia.

The extremely high levels of
melatonin observed in patients suffering from narcolepsy and therefore with REM
sleep deprivation have led some to suggest an etiologic link between hormone and sleep disorder.
Melatonin has been proposed as a treatment for narcolepsy. but no clinical
trials have been undertaken.

REM sleep onset is associated
with increased melatonin levels, which may be due to increased norepinephrine
release associated with the increased autonomic activity. Oral administration of
melatonin in gelatine was associated with a decreased subjective feeling of jet
lag in aeroplane travellers.

A more recent double-blind,
placebo-controlled study of a small group of police officers working for seven
consecutive night shifts found improved performance in various letter-target and
visual search tests after melatonin was administered. Melatonin
administration is also associated with prolonged time needed for animals to
emerge from the effects of barbiturates and with decreased anxiety-inducing
behaviours. It decreases alertness and increases sleepiness in animals.

Exogenous melatonin
administration is associated with decreased epileptiform activity in
animal models of epilepsy. Pinealectomy in these animals produces increased
seizure activity. Antimelatonin antibodies have been shown to have an
epileptogenic effect in rats. Evidence from humans supports the findings that
melatonin increases sleep, decreases motor activity, and decreases paroxysmal EEG activity observed in epileptic
patients.

Evidence that melatonin is
anticonvulsive is that pinealectomy results in seizures in experimental animals.
Recent studies with magnetoencephalography have shown an apparent proconvulsive
effect of melatonin. This would be consistent with the observed five- to
eight-fold higher levels of plasma melatonin observed at night than during the
day. Seizures are also more frequent during pregnancy, when melatonin levels are
higher. Anticonvulsants that decrease melatonin secretion, such as the
benzodiazepines, may exert their antiepileptic activity by attenuating
nocturnal melatonin secretion.

In rats the period associated
with the development of enkephalin-induced seizures coincides with the peak of
melatonin plasma levels at 3 weeks of age; therefore, it is proposed that
melatonin mediates the anticonvulsant action of drugs effective for petit-mal
(absence) epilepsy and that the pineal gland is implicated in the pathogenesis
of this form of childhood epilepsy . In addition, a relationship between
pineal calcification and the laterality of temporal lobe seizures has been
proposed, based on the fact that the pineal receives predominant limbic input
from the right temporal lobe, which itself has greater limbic and reticular
input than the left temporal lobe.

The mechanisms for melatonin's
sedative and antiepileptogenic effects remain obscure but may be due to
interactions with the serotonergic and/or GABA-ergic neurotransmitter systems.
Benzodiazepines have been demonstrated to have a stimulatory effect on
acetyltransferase.

Artificial magnetic fields may
attenuate seizure activity by altering the functioning of the pineal gland and
melatonin levels. Humans kept under bright light during the night will show
deterioration in parameters measuring performance in spite of decreases in
their melatonin level; this suggests that these parameters worsen for other
reasons.

Other Behavioural Effects

Nociceptive responses have been
significantly diminished by functional pinealectomy (induced by a single
long-light-duration day). Oral melatonin administration restored the pain
response.

Aggression is decreased after
pinealectomy and increased again when melatonin is administered. Ethanol
preference does not seem to be affected by pinealectomy. Passive avoidance is
increased with a pineal extract. Social isolation induces pineal hypertrophy.
Stress leads to increased production of melatonin and tryptophan uptake by the
pineal. A dramatic demonstration of the probable link between psychology and
pineal physiology is the observed alteration in NAT activity observed in rat
pups deprived of maternal contact.

Melatonin is known to decrease
activity in the SCN and reticular formation. Melatonin may be involved in
certain mental processes and has been implicated in mental illnesses, such as
cyclic affective disorders.

The pineal and melatonin seem to
interact with several psychiatric drugs, especially antidepressant and
antipsychotic medications that operate on the
beta-adrenergic system. Chlorpromazine and haloperidol inhibit HIOMT, the
responsible enzyme. Chronic lithium administration suppresses a shift in the
peak night-time melatonin concentration and decreases hormone levels.

In patients with no cortisol
response to administration of dexamethasone, there may be a pineal factor that
stimulates the production of corticotropin-releasing factor by inhibiting its
action. Depressed patients with an abnormal dexamethasone suppression test result have lower-than-normal
melatonin levels. Low melatonin levels have been suggested to indicate a genetic
trait for depression. These abnormalities have been correlated with other
changes in the hypothalamic-pituitary-adrenal axis. Patients with low melatonin
levels also often have early escape on dexamethasone suppression testing.

Melatonin is increased in mania,
which is consistent with a condition associated with increased sympathetic
activity. There is a possible relationship between pineal hormonal activity and
eating disorders, such as anorexia nervosa. It is unclear if the abnormalities
are the cause or effect of the psychopathologic process.

Seasonal affective disorder
(SAD), recently popularized in the media, is a condition associated with onset
of depression during winter, with its longer periods of darkness. Exposure of
SAD patients to several hours of
bright light lowers circulating levels of melatonin and concomitantly elevates
mood. Whether the two effects are coincidental or causally related is under
investigation.

A patient with both SAD and
cocaine addiction was described. SAD is related to disorders in circadian
rhythms, and cocaine addiction may be related to disorders of melatonin. The two
conditions may thus both be linked through the pineal.

Investigators of the causes of
the sudden infant death syndrome (SIDS) have suggested that the
pineal acts as the "masterswitch of life and death" through neurohormonal
regulation and neural connections with the hypothalamus: it acts especially
through its influence on hypothalamic noradrenaline levels that contribute to
SIDS by influencing the function of the autonomic nervous system, specifically
the control of such vital functions as breathing.

Although other infra- and
ultradian cycles influence behaviour, the light-dark variation is the most
blatantly regulatory cycle in humans. The sensitivity of melatonin production
and release to environmental light was demonstrated in a study that followed serum melatonin levels in night
shift workers in Antarctica. A period of night shift work
requires readaptation of melatonin rhythms. This study shows that the time taken
to adapt is longer (3 weeks) in winter than in summer (1 week). This has
important implications for shift workers
in temperate zones. A study of melatonin levels in a population living at a
latitude of 70 degrees with almost continuous darkness in winter and almost
continuous light in summer, showed the highest levels in January and the lowest
in June.

Serotonin may contribute to an
antidepressant effect of the pineal. Forced swimming, a test of immobility in
rats (and an animal model for depression), was
improved following the transplant to the frontal neocortex of pineal tissue.

Analysis of CT scans showed
increased pineal calcification in premenopausal schizophrenic women. This
suggests a link between pineal activity (presumably decreased in the presence
of calcification) and schizophrenia.

Because of relationships between
melatonin and physiologic processes associated with arousal, manipulations of
melatonin levels through imposed magnetic fields have been proposed for
disorders of sleep and for epilepsy.

Sandyk noting the seasonal and
possibly cyclic occurrence of cluster headaches and to a lesser extent migraine
headaches, believes that the pineal and melatonin may be involved in their
pathogenesis. He cites successful treatment of a patient with migraine with picoTesla
magnetic fields.

An important consideration in
any therapeutic intervention with melatonin will be mode of delivery. An oral
melatonin regimen in rats was found to be effective in re-establishing normal
circadian levels of urinary 6-sulphatoxymelatonin in functionally
pinealectomized rats.

Conclusion

The pineal enables the organism
to coordinate its activities with cyclic variations in the physical environment.
This is achieved primarily through links between the pineal and the
photoreceptor organs as well as interrelationships between the gland and the
information-processing neuroendocrine system. An interesting question for
neurosurgeons to ponder is why lesions that destroy or increase pineal tissue
seem to be associated more with mechanical effects on adjacent brain tissue and
CSF circulation than with alterations in physiology. The pineal is a modulator,
not a primary mover in the physiologic engine.

From the little structure that
seemed to do nothing except give rise to difficult tumors, the pineal has
emerged as a central organ in human physiology. Consistent with the evolving
holistic picture of the organism, the pineal defies
understanding if conceptually relegated to one system or function. The updated
concept of the soul is that of a dynamically interacting totality in which the
pineal may exert an important if not dominant role, entitling it to a share of
the throne on which Descartes placed it.